Effects on the Isolated Human Bronchus of SR 48968, a Potent and Selective Nonpeptide Antagonist of the Neurokinin A (NK<sub>2</sub>) Receptors

Advenier, C.; Naline, Emmanuel; Toty, L.; Bakdach, H; Emonds‐Alt, Xavier; Vilain, P.; Jc, Brelière; G, Le Fur

doi:10.1164/ajrccm/146.5_pt_1.1177

Cited by 99 publications

(69 citation statements)

References 13 publications

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“…Classically, the expression of NK 1 R and NK 2 R has been described in both the nervous system and peripheral target organs, including human airways, whereas the expression of NK 3 R was believed to be more limited to the central and peripheral nervous system (31,34). Furthermore, it has traditionally been thought that only the NK 2 R mediated direct contraction of airway smooth muscle, especially in human airways (3).…”

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confidence: 99%

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Expression and coupling of neurokinin receptor subtypes to inositol phosphate and calcium signaling pathways in human airway smooth muscle cells

Mizuta

Gallos

Zhu

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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Emala CW Sr. Expression and coupling of neurokinin receptor subtypes to inositol phosphate and calcium signaling pathways in human airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 294: L523-L534, 2008. First published January 18, 2008 doi:10.1152/ajplung.00328.2007.-Neuropeptide tachykinins (substance P, neurokinin A, and neurokinin B) are present in peripheral terminals of sensory nerve fibers within the respiratory tract and cause airway contractile responses and hyperresponsiveness in humans and most mammalian species. Three subtypes of neurokinin receptors (NK 1R, NK2R, and NK3R) classically couple to G q protein-mediated inositol 1,4,5-trisphosphate (IP3) synthesis and liberation of intracellular Ca 2ϩ , which initiates contraction, but their expression and calcium signaling mechanisms are incompletely understood in airway smooth muscle. All three subtypes were identified in native and cultured human airway smooth muscle (HASM) and were subsequently overexpressed in HASM cells using a human immunodeficiency virus-1-based lentivirus transduction system. Specific NKR agonists {NK 1R, [Sar 9 ,Met(O2) 11 ]-substance P; NK 2 R, [␤-Ala 8 ]-neurokinin A(4 -10); NK 3 R, senktide} stimulated inositol phosphate synthesis and increased intracellular Ca 2ϩ concentration ([Ca 2ϩ ]i) in native HASM cells and in HASM cells transfected with each NKR subtype. These effects were blocked by NKR-selective antagonists (NK 1R, L-732138; NK2R, GR-159897; NK 3R, SB-222200). The initial transient and sustained phases of increased [Ca 2ϩ ]i were predominantly inhibited by the IP3 receptor antagonist 2-aminoethoxydiphenyl borate (2-APB) or the store-operated Ca 2ϩ channel antagonist SKF-96365, respectively. These results show that all three subtypes of NKRs are expressed in native HASM cells and that IP 3 levels are the primary mediators of NKR-stimulated initial [Ca 2ϩ ] i increases, whereas store-operated Ca 2ϩ channels mediate the sustained phase of the [Ca 2ϩ ]i increase. intracellular calcium; ryanodine; actin; myosin; lentivirus TACHYKININS ARE STORED AND RELEASED from unmyelinated pulmonary C fibers in airways (8,30,31,44) and evoke inflammatory peripheral effects including vasodilation, plasma extravasation, leukocyte adhesion, facilitation of cholinergic neurotransmission, and epithelial cell secretion in the airways (1, 12, 16), which are referred to as neurogenic inflammation. Local release of tachykinins from peripheral sensory nerves may also lead to airway contractile responses and hyperresponsiveness in human and most mammalian species (32, 42). At least three subtypes of neurokinin receptors (NK 1 R, NK 2 R, and NK 3 R) have been characterized, which exhibit preferential affinity for the endogenous neuropeptides substance P, neurokinin A, and neurokinin B, respectively (33). All three receptor subtypes are members of the seven-transmembrane domain receptor superfamily that couple to G q proteins (50).Classically, the expression of NK 1 R and NK 2 R has been described in both the nervous system and p...

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confidence: 99%

“…Furthermore, it has traditionally been thought that only the NK 2 R mediated direct contraction of airway smooth muscle, especially in human airways (3). However, recently it was reported that in smalldiameter human bronchi, tachykinins also cause contraction via NK 1 R stimulation (4).…”

mentioning

confidence: 99%

Expression and coupling of neurokinin receptor subtypes to inositol phosphate and calcium signaling pathways in human airway smooth muscle cells

Mizuta

Gallos

Zhu

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Although NK 2 receptors play a prominent role in the bronchoconstrictor effect of tachykinins [7], NK 1 receptors can also mediate the bronchoconstriction, especially due to their presence in the small-and medium-sized bronchi. Immune histochemistry has demonstrated the presence of both NK 1 and NK 2 receptors in the smooth muscle of the human lung.…”

Section: Drug Safetymentioning

confidence: 99%

“…Of all these effects, bronchoconstriction is the most studied effect [5]. Asthmatic [6] patients are more sensitive to the bronchoconstrictor effect of substance P and NKA [7][8][9]. Studies on isolated human airways have shown that tachykinin-induced bronchoconstriction is mainly caused by activation of the tachykinin NK 2 receptor [7].…”

Section: Introductionmentioning

confidence: 99%

“…Asthmatic [6] patients are more sensitive to the bronchoconstrictor effect of substance P and NKA [7][8][9]. Studies on isolated human airways have shown that tachykinin-induced bronchoconstriction is mainly caused by activation of the tachykinin NK 2 receptor [7]. However, contraction of the small-and medium-sized human bronchi can also be mediated by tachykinin NK 1 receptors [10,11].…”

Section: Introductionmentioning

confidence: 99%

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The triple neurokinin-receptor antagonist CS-003 inhibits neurokinin A-induced bronchoconstriction in patients with asthma

Schelfhout

Louis

Lenz

et al. 2006

Pulmonary Pharmacology & Therapeutics

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Abstract:Neurokinin A (NKA) causes bronchoconstriction in asthmatic patients. In vitro both NK 1 and NK 2 receptors can mediate airway contraction. Moreover in guinea pigs, NK 3 receptors facilitate cholinergic neurotransmission. Dual tachykinin NK 1 /NK 2 receptor antagonism results in prevention of NKA-induced bronchoconstriction. We have now examined the effect of a single dose of the triple tachykinin receptor antagonist CS-003 on NKAinduced bronchoconstriction in asthmatics.A double blind, crossover, placebo-controlled trial in 16 mild asthmatics was performed. One single dose of CS-003 (200 mg, solution in distilled water) or matched placebo was given orally on the assessment days. NKAprovocation tests were performed pre-dose and 1,8 and 24 h after dosing.There was a significant shift to the right of the dose-response curve at 1 and 8 h after intake of CS-003. PC 20 was not reached in 12/16 patients at 1 h post-dose and in 5/16 patients at 8h post-dose. This did not occur under placebo treatment.A single dose of 200 mg CS-003 protected significantly against NKA-induced bronchoconstriction at 1 and 8 h post-dose in mild asthmatics.

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The airways pharmacology of DNK333, a potent, selective, non‐peptide dual NK₁/NK₂ receptor antagonist

Lewis

El-Hashim

Gerspacher

et al. 2004

Drug Development Research

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The airways' pharmacology of DNK333 ((1R,3R,2E)-N-[3,4-dichlorobenzyl)]-4-[(hexahydro-2-oxo-1H-azepin-3-yl)amino]-N-methyl-3,5bis(trifluoromethyl) benzamide), a potent and selective dual NK 1 / NK 2 neurokinin receptor antagonist is described in the present paper. DNK333 bound with high and similar affinities to human NK 1 and NK 2 receptors. In guinea-pig isolated trachea, DNK333 induced concentrationdependent blockade of the contractile responses to NK 1 -or NK 2 -receptor agonists. In anaesthetized guineapigs, DNK333 shifted the bronchoconstrictor dose-response curves induced by NK 1 -and NK 2 -receptor agonists by 21.8-(3 mg/kg) and 6.8-fold (10 mg/kg), respectively. At 10 mg/kg, a 12-h duration of action was observed. Nasal perfusion of substance P and capsaicin to anaesthetized guinea-pigs induced extravasation, which was inhibited dose-dependently by DNK333 (ED 50 values 72 and 70 mg/kg, respectively). Exposure of conscious guinea-pigs to 0.6 M citric acid resulted in cough and an increase in enhanced pause of respiratory function (Penh). Oral administration of DNK333 (0.3, 3, or 10 mg/kg, À2 h) inhibited cough by 62, 63, and 82%, respectively and the increase in Penh by 85.5 and 77.2% (3 and 10 mg/kg, respectively). Bronchoconstrictor responses in anaesthetized guinea-pigs to intravenous injections of methacholine and substance P were increased 60 min after LPS challenge (1 mg/kg, i.v.). DNK333 (1 and 10 mg/kg) dosed intraduodenally 30 min prior to LPS challenge inhibited airway hyperreactivity in a dose-dependent manner.In conclusion, DNK333 is a potent, orally bioavailable, dual NK 1 /NK 2 receptor antagonist with a long duration of action. It inhibits bronchoconstriction, extravasation, cough, and airway hyperreactivity induced by endogenous release of neuropeptides, which renders DNK333 suitable for exploring the role of tachykinins in respiratory disease.

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Effects on the Isolated Human Bronchus of SR 48968, a Potent and Selective Nonpeptide Antagonist of the Neurokinin A (NK₂) Receptors

Cited by 99 publications

References 13 publications

Expression and coupling of neurokinin receptor subtypes to inositol phosphate and calcium signaling pathways in human airway smooth muscle cells

Expression and coupling of neurokinin receptor subtypes to inositol phosphate and calcium signaling pathways in human airway smooth muscle cells

The triple neurokinin-receptor antagonist CS-003 inhibits neurokinin A-induced bronchoconstriction in patients with asthma

The airways pharmacology of DNK333, a potent, selective, non‐peptide dual NK₁/NK₂ receptor antagonist

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Effects on the Isolated Human Bronchus of SR 48968, a Potent and Selective Nonpeptide Antagonist of the Neurokinin A (NK2) Receptors

Cited by 99 publications

References 13 publications

Expression and coupling of neurokinin receptor subtypes to inositol phosphate and calcium signaling pathways in human airway smooth muscle cells

Expression and coupling of neurokinin receptor subtypes to inositol phosphate and calcium signaling pathways in human airway smooth muscle cells

The triple neurokinin-receptor antagonist CS-003 inhibits neurokinin A-induced bronchoconstriction in patients with asthma

The airways pharmacology of DNK333, a potent, selective, non‐peptide dual NK1/NK2 receptor antagonist

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Product

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Effects on the Isolated Human Bronchus of SR 48968, a Potent and Selective Nonpeptide Antagonist of the Neurokinin A (NK₂) Receptors

The airways pharmacology of DNK333, a potent, selective, non‐peptide dual NK₁/NK₂ receptor antagonist